ABSTRACT Antiretroviral therapy (ART) fundamentally altered the lives of people living with HIV-1 by shifting the disease course from rapid progression to AIDS and death to a manageable chronic disease. However, ART- treated people still experience higher rates of morbidity and mortality than the general population. As more people are treated with ART and the HIV-1 treated population ages we need new strategies to normalize their life span and quality of life. Therefore, research is needed to elucidate the biological processes underying the heightened risk of morbidity and mortality and to translate this knowledge into new treatments. This proposal seeks to evaluate how immune activation during HIV-1 infection contributes to increased mortality and morbidity, and how this knowledge can be translated into novel treatments. Following all viral infections, acute immune responses are critical for reducing virus levels. Subsequently, those responses are turned off. In HIV-1 infection, however, heightend immune activation persists even after virus levels are reduced to very low levels by ART?those immune responses are never turned off. Over time, persistant activation exhausts the immune system, clearing the way for more viral replication, opportunistic infections and AIDS. One contributing factor to chronic immune activation during HIV-1 is that expression of IFN stimulated genes (ISGs) is persistently up-regulated. Humans carry hundreds of ISGs with many functions including direct antiviral activity and regulation of other ISGs and immune responses. Our group has documented that ISG levels are persistently increased during HIV-1 infection. We hypothesize that targeting specific ISGs may be a strategy for reducing chronic immune activation during HIV-1 infection while allowing other compontents of the immune response to remain effective. The objective of this proposal is to identify ISGs contributing to chronic immune activation during HIV-1 infection and to translate those data into a ranked list of existing drugs that could repurposed as adjunctive treatments with ART. To do so, we will measure ISG expression among HIV-1 infected indivuals before and after initiation of ART, and will compare their ISG expression levels to uninfected participants. Among the HIV- 1 infected participants, we will also determine how ISG expression relates to clinical HIV-1 parameters and immunologic markers. In order to more clearly define the role of ART on ISG expression we will also conduct in vitro studies in which we directly treat cells from HIV-1 infected individuals with ART and compare ISG expression before and after treatment. These studies will provide detailed information about the effects of ART use on ISG levels and immune activation by reducing viral replication and direct effects of the drugs themselves. Finally, we will integrate data from our studies of ART and ISG expression with data regarding gene expression during other infections and drugs that can be used to treat those other infections. By doing so, we aim to identify drugs that can be repurposed to treate chronic immune activation during HIV-1 infection.